'IMMUNITY OF SCHISTOSOME GLYCOCONJUGATES'

University Of Oklahoma Hlth Sciences Ctr, Oklahoma City OK

Investigators

Linked publications & trials

Abstract

DESCRIPTION (Adapted from the applicant's Abstract): Schistosomiasis is a worldwide parasitic disease caused by blood flukes of the Schistosoma genus. In preliminary studies to this revised application, we investigated the major immune response to parasite-derived antigens in rodents and primates infected with S. mansoni, S. japonicum and S. haematobium. Our results show that infection with schistosomes induces major IgM, IgG, IgA and IgE responses to glycan-based (carbohydrate-based) antigens on soluble and membrane glycoproteins derived from the worms. So far we have identified five major antigenic glycans in bi- and trisaccharide sequences containing fucose, galactose, xylose, N-acetylglucosamine and N-acetylgalactosamine. The antigens are designated the Lewis x (Le'), lacdiNAc (LDN), fucosylated LDN (LDNF), core-Xylose and core-Fucose. We hypothesize that specific anti-glycan antibodies in schistosome-infected animals may provide protective immunity against the parasite. We will test this hypothesis and develop more information about immunity to schistosome glycans, their biosynthesis, and developmental regulation. (Aim 1) We will synthesize a panel of novel oligosaccharides containing the novel schistosome glycan epitopes by semi-synthetic chemistry using purified and recombinant glycosyltransferases, and conjugate these glycans to protein carriers to test their recognition by sera from infected animals using ELISA. (Aim 2) We will develop new diagnostic immunoassays to detect for the presence of (a) antibodies to schistosome glycoconjugates and (b) circulating schistosome glycoconjugates using available monoclonal antibodies (mabs) and additional mabs to be developed to these glycan antigens. (Aim 3) We will study the immunity developed toward schistosome glycoconjugates upon infection with different numbers of cereariae. We will define the expression and localization of schistosome glycan antigens at all stages of development in the vertebrate hosts. (Aim 4) We will test the protective effects of antibodies to specific glycans using passive transfer experiments employing defined mabs, affinity purified antibodies from sera of infected animals, and antisera depleted of specific antibodies by absorption to defined glycans. (Aim 5) Finally, we will immunize mice with specific glycan conjugates and evaluate the in vivo protective capacity of these conjugates upon cercarial challenge and also by passive transfer experiments. These studies will give new information about the fundamental nature of immunity to glycan antigens in schistosome-infected animals and provide new reagents to test the ability of glycan conjugates to prevent this disease.